Hydrogen Gas Attenuates Toxic Metabolites and Oxidative Stress-Mediated Signaling to Inhibit Neurodegeneration and Enhance Memory in Alzheimer's Disease Models.

Abstract

Alzheimer's disease (AD) involves amyloid-beta (Aβ) plaque-driven oxidative stress and neuroinflammation leading to memory impairment. Reactive astrocytes further contribute to neurodegeneration through toxic metabolite accumulation within the astrocytic urea cycle. This study examined whether 3% hydrogen gas (H2) inhalation over 60 days could counteract these processes in 5xFAD mice (n=14) and wild-type controls (n=15). Cognitive performance was assessed via Morris water maze and Y-maze tests. Hippocampal ammonia and hydrogen peroxide levels were quantified biochemically, and Aβ, GABA, and inflammatory marker expression were evaluated by immunohistochemistry and qRT-PCR in both mouse hippocampi and Aβ oligomer-treated primary astrocytes. H2-treated 5xFAD mice showed significant reductions in cognitive deficits, oxidative stress markers, toxic metabolite accumulation, and inflammatory signaling compared with vehicle controls, suggesting that H2 inhalation modulates the astrocytic urea cycle to limit neurodegeneration.

Mechanism

H2 inhalation suppresses accumulation of toxic metabolites (ammonia and hydrogen peroxide) in the astrocytic urea cycle, thereby attenuating oxidative stress and Aβ-associated inflammatory signaling to limit neurodegeneration.